Regulatory Issues Affecting Cardiologists in Europe

The field of cardiology has seen an unprecedented level of development in recent years both in terms of new therapeutic agents and devices. The field of cardiovascular therapeutics is fast approaching the state of an 'all inclusive area' with the overlap of areas such as diabetes and lipids.

With advent of the recent changes to European pharmaceutical regulations, including the clinical trial directive, development of interventional agents (drugs, devices or a combination) is perceived to be under greater regulatory scrutiny. This has the following effects or advantages:

for medicinal products, it offers a centralised process through the European Medicines Agency (EMEA) with the potential to authorise a product through out the EU in a single attempt;

there is greater debate and interaction between practitioners and agencies across Europe with the attendant consistency in the evaluation process; and

the time taken for the regulatory process is more uniform.

National authorisations remain the alternative option.

With the advantages come increased demands on the development process and practice. For example, industry and academia have the responsibility of conducting organised and planned clinical trials with the generation of robust data, including pre-clinical and clinical data. The clinical trials directive of 2004 requires detailed recordings of all clinical trials, both industry- and academia-led, and registration of all trials with a community trial number.

Such regulatory requirements do not necessarily limit mechanistic studies, nor do they dictate the design of the study, but induce more controlled evaluation of the effect of an intervention (drug or device). Indeed, the main change has been awareness regarding the regulations, as they were already in place previously.

There is now a greater expectation to use hard end-points such as mortality (all-cause or specific cause) in place of surrogate end-points. In some instances validated surrogate markers are still used. The trials therefore may require large sample sizes, often in the thousands, to achieve the above and get approval for a particular indication.

Some of the examples are: the Heart Outcomes Prevention Evaluation (HOPE) trial, the Candesartan in Heart Failure Assessment of Reduction in Morbidity and mortality (CHARM) trial, the Valsartan Heart Failure Trial (VAL-HeFT) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, and trials with statins (Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), 4S), etc. Other examples include treatments for acute and chronic heart failure (HF) that are expected to fulfil the regulatory requirements.

Similar considerations govern the development of devices or drug-device combinations. For example, coronary stents, especially coated stents (sirolimus or paclitaxel), are expected to provide long-term benefit, i.e., clinically event reduction. Pacemaker and defibrillator studies are expected to be designed with a view to demonstrating a prognostic benefit, either in terms of mortality or improvements in appropriately measured quality of life.

There is a greater emphasis placed on the safety of the intervention and this impacts reporting of such events both during the trial and in clinical practice. A number of measures (pharmacovigilance and risk management activities) are in place to ensure this, including efforts to make practitioners aware of this.

A number of guidelines that govern drug and device development are publicly available on the EMEA website (www.emea.eu.int).

Impact on Clinical Practice

The changes in the regulatory requirements have imposed a certain level of responsibility on the physician/cardiologist to evaluate the overall risk-benefit ratio of the intervention, and for each patient in particular. The actions/prescriptions are therefore likely to be under greater scrutiny both by professional bodies and the public.

Public awareness of regulatory requirements and options is also on the increase, and this will only encourage 'considered decision-making' and patient involvement. Last, but not the least, the Freedom of Information Act is indeed producing a greater impact on public awareness, clinical practice demands and the publication of data, including adverse events.

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